Interesting news continues to emerge from the data collected by the folks at Gilead Sciences in their pivotal trial GS 99-903. Dr. Joel Gallant, in this late breaker presentation, once again reviewed the preliminary results at 48 weeks from this study (safety and efficacy data were presented at the International AIDS Conference in Barcelona). But this time, new information on the lipid and mitochondrial DNA profile were added to the presentation.

In this study, 600 patients were randomized 1:1 to receive either stavudine (d4T, Zerit) or tenofovir (TDF, Viread) both in combination with lamivudine (3TC, Epivir) and efavirenz (EFV, Sustiva). Baseline demographic characteristics were well matched in both groups, with approximately 40 percent of the subjects having baseline CD4 counts below 200 and HIV-1 RNA levels above 100,000 copies.

The efficacy data was previously discussed in the GS-99-903 coverage from Barcelona. In a nutshell, there were no differences between the tenofovir and stavudine arms, with 87 percent of the subjects in both arms achieving a viral load (VL) less than 400 at 48 weeks by intent-to treat analysis (in which missing information was counted as failure). Using the less than 50 copies assay, the results were 81 percent for the tenofovir arm and 82 percent for the stavudine arm. There was also a robust increase in CD4 cell counts in both groups (169 in the tenofovir arm and 167 in the stavudine arm). Stratification of data by VL below and above 100,000 copies did not show any differences between arms.

The discontinuation rate in this study was strikingly very low (less than 10 percent) with no differences between arms in respect to specific reasons for discontinuation. There were also no significant differences between the onset of grade 3 and 4 adverse events or laboratory abnormalities, with the exception of triglyceride levels.

In the stavudine arm, there was a greater increase in fasting lipid levels, including triglycerides, total cholesterol, and LDL cholesterol. The non-fasting lipid values were reported also to be very similar.

Dr. Gallant then summarized the in vitro data that previously demonstrated minimal inhibition of gamma DNA polymerase, which synthesizes mitochondrial DNA in multiple cell types. In those studies, the effect of tenofovir on gamma DNA polymerase was similar to what has been seen with lamivudine.

In one of those studies, the investigators compared mitochondrial DNA levels in tenofovir- and stavudine-treated patients with a group of HIV-negative male historical controls. At baseline, mean mitochondrial DNA levels were lower in both arms of the study than compared to the controls. However, at 48 weeks, there was a significant increase in DNA levels in tenofovir-treated patients, which was not seen in the stavudine arm.

Dr. Gallant explained those findings by quoting other studies that have found mitochondrial DNA levels to be lower in HIV-infected patients than in HIV-negative individuals. Antiretroviral therapy may then restore (i.e., increase) mitochondrial DNA levels, but the effect may be blunted in the stavudine-treated patient because of drug-related mitochondrial toxicity.

Dr. Gallant then described the results of another substudy analysis in which tenofovir-treated patients had lactic acid levels below the upper limit of normal, in comparison to patients in the stavudine arm with statistically significant abnormal levels. In addition, patients in the stavudine arm were found to have a higher incidence of nucleoside analog toxicity such as peripheral neuropathy and investigator-defined lipodystrophic changes.

As we previously learned, the preliminary efficacy study clearly demonstrates that tenofovir and stavudine (in combination with lamivudine and efavirenz) are highly potent. There is really no reason to suspect that long-term durability in the tenofovir group will be a concern. This study is scheduled to continue blinded for three years, so at the end of that period we will have that answer. What appears more intriguing over time is the discrepancy in lipid abnormalities, some of the in vitro data, and the nucleoside associated toxicities between both groups. Follow up will determine if the abnormalities seen in the stavudine group will translate into unwanted clinical outcomes.

It is exciting to see the drug development of new agents that appear to be at least equally effective as previous agents while less toxic. Long-term follow up will tell if tenofovir is indeed as good tomorrow as it appears to be today.

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